Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

Mol Metab. 2016 Jan 2;5(3):171-183. doi: 10.1016/j.molmet.2015.12.004. eCollection 2016 Mar.


Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes.

Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing.

Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding.

Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

Keywords: Epigenetics; Glucose; Lipid; Liver; Obesity; Type 2 Diabetes.